Cathepsin D is a lysosomal protease that has been associated with several biological processes of therapeutic significance such as protein catabolism, degenerative diseases and breast cancer progression.The X-ray structure of human cathepsin D as well as its complex with pepstatin A have been recently determined at 2.5 _ resolution. We have studied the association of the inhibitor to the enzyme using high-sensitivity isothermal titration calorimetry. The experiments were performed at pH 3.6 where the association constant is known to be maximal. The tight-binding association reaction was characterized by a positive enthalpy change at low temperatures and a constant and negative heat capacity change what makes the enthalpy change to reverse its sign around room temperature. The dissociation constant at room temperature is around 4 pM (~ G = -15.6 kcal/mol ) indicating that the binding reaction is entropically driven. In order to obtain a complete picture of the molecular recognition process, the dependence of both the enthalpy and the association constant with the pH will be studied, allowing us to discuss if the binding process induce any change in the protonation state of the protein. This experimental information will be compared with the structure-based thermodynamic calculations currently being carried out in our laboratory. This comparison between experimental and calculated energetics will allow us not only to refine the empirical parameters used in our calculations but also to improve our understanding of the inhibition mechanism at an atomic level which would lead to the development of new strategies in the design of new inhibitors specific towards a certain enzyme within the aspartic proteinase family.